Disease-modifying therapies for tauopathies: agents in the pipeline

ABSTRACT

Introduction: Tauopathies are heterogeneous clinicopathological entities characterized by abnormal neuronal and/or glial inclusions of the microtubule-binding protein tau. Primary tauopathies considered to be diseases correspond to a major class of frontotemporal lobar degeneration (FTLD) neuropathology (FTLD-Tau), including several forms of frontotemporal dementia (FTD) clinical syndromes. Little progress has been made in the past 20 years in developing effective disease-modifying drugs for primary tauopathies and available symptomatic treatments have limited efficacy.

Areas covered: Potential disease-modifying drugs in clinical development to slow neuropathological progression of primary tauopathies.

Expert opinion: Since the underlying pathology of primary tauopathies consists of abnormal tau protein aggregates, treatments are being developed to interfere with the aggregation process or to promote the clearance of this protein. Unfortunately, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. Further evidence will come from ongoing Phase I/II trials on novel drugs and immunotherapeutics with various targets – prevention of deposition or removal of tau aggregates, inhibition of tau phosphorylation/acetylation, modulation of O-GlcNAcylation, activation of autophagy or ubiquitin-proteasome system pathways, and rescue of selected tau loss of function or suppression of tau gene expression.

KEYWORDS:

• Dementia
• primary tauopathies
• frontotemporal dementia
• frontotemporal lobar degeneration
• tau protein
• progressive supranuclear palsy
• corticobasal degeneration
• primary age-related tauopathy
• aging-related tau astrogliopathy

Article highlights

• Tauopathies are a heterogeneous group of neurodegenerative diseases characterized by the presence of brain cells harboring inclusions of pathological species of tau protein.

• Primary tauopathies considered to be diseases mainly correspond to a major class of frontotemporal lobar degeneration (FTLD) neuropathology, i.e. FTLD-Tau.

• FTLD-Tau encompasses a spectrum of neurodegenerative diseases including several forms of frontotemporal dementia (FTD) clinical syndromes, i.e. the behavioral variant of FTD (bvFTD), primary progressive aphasia variants, progressive supranuclear palsy syndrome, and corticobasal syndrome.

• The terms progressive supranuclear palsy and corticobasal degeneration are now reserved for neuropathological diagnosis, since the clinical phenotype of these entities can show a wide range of presentations, including those with a purely motor disorder.

• The lack of accurate biomarkers to identify and track the progression of these neurodegenerative diseases has slowed therapeutic development in tauopathies.

• A recently completed Phase III trial of a compound targeting tau protein aggregation (LMTM) in bvFTD patients showed negative findings.

• Further evidence on disease-modifying treatments will come from ongoing Phase I and II trials of novel drugs and immunotherapeutics with various targets – prevention of deposition or removal of tau aggregates, modulation of tau phosphorylation/acetylation/O-GlcNAcylation, and rescue of selected tau loss of function or suppression of tau gene expression.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.